Gastroesophageal Reflux Disease and Barrett Esophagus in the Elderly - BINASSS
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G a s t ro e s o p h a g e a l R e f l u x
Disease and Barrett
Esophagus in the Elderly
a, b
Fouad Otaki, MD *, Prasad G. Iyer, MSc
KEYWORDS
Gastroesophageal reflux disease GERD Barrett esophagus
Esophageal adenocarcinoma Elderly
KEY POINTS
The early diagnosis and optimal management of elderly patients is vital to the delivery of
high quality care in an aging patient population.
Maintaining a low threshold is essential given atypical presentations and increased reper-
cussions of a delayed or missed diagnosis.
Contextualizing a discussion regarding management of complications and treatments in
the elderly should be personalized and account for patient comorbidities.
Novel minimally invasive screening, surveillance and treatments of GERD and Barrett’s
esophagus have allowed us to manage a larger at-risk elderly patient population.
INTRODUCTION
An aging population is a global phenomenon, with minor regional variations in the de-
mographic transition. Average life expectancy continues to increase and many coun-
tries are experiencing population contraction and decreasing fertility. Nine percent of
the world’s population was older than 65 years in 2015, and that proportion is pro-
jected to increase to 17% by 2050.1 This pattern is evident in North America, which
is second only to Europe as the oldest region, with 21.4% of population being 65 years
or older. In fact, 20 million individuals will be older than 85 years in 2050.2
This demographic change is also affecting the way we diagnose and manage the
most common upper gastrointestinal indication for primary care physician clinic visits,
gastroesophageal reflux disease (GERD). GERD is defined as reflux of gastric contents
Funding: Supported in part by NIH, USA R01 grant CA 241064 (to P.G. Iyer).
a
Division of Gastroenterology and Hepatology, Oregon Health and Science University, L461,
3181 SouthWest Sam Jackson Park Road, Portland, OR 97229, USA; b Barrett’s Esophagus Unit,
Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SouthWest,
Rochester, MN 55905, USA
* Corresponding author.
E-mail address: otaki@ohsu.edu
Clin Geriatr Med 37 (2021) 17–29
https://doi.org/10.1016/j.cger.2020.08.003 geriatric.theclinics.com
0749-0690/21/ª 2020 Elsevier Inc. All rights reserved.
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Inc. Todos los derechos reservados.18 Otaki & Iyer
into the esophagus, oropharynx, nasopharynx, larynx, or lungs with resultant symp-
toms and complications.3 Heartburn, manifest as epigastric burning with radiation
to the chest or neck, is a common typical symptom.3 It is estimated that one-fifth of
the adult Americans population experiences heartburn at least once a week, with 15
million suffering from symptoms on a daily basis.4 Original studies indicated increasing
incidence of GERD with age, with 6% to 17% of the elderly US population reporting
these symptoms.5 GERD also accounts for nearly a quarter of primary care physician
visits for patients 65 years or older,6 and it is the sixth most common disorder in
nursing home residents.7
Various studies have attempted to identify the frequency of esophageal mucosal
injury in GERD, and overall incidence for esophagitis varied from 6.4% to 15.5% in
population studies.8 Severe reflux esophagitis was more prevalent (37%) in patients
70 years or older in a population study of 12,000 patients compared with 12% in pa-
tients 21 year old or younger.9 This likely underrepresents the at-risk cohort, given
impaired sensory function with age. Patients 65 years or older have shown to have
decreased and delayed reporting of balloon esophageal distention10 and sensitivity
to esophageal acid perfusion.11
Not only is GERD more common, but the presentation is often atypical and more se-
vere in the elderly. Atypical symptoms include dyspepsia, epigastric pain, anorexia,
dysphagia, odynophagia, weight loss, anemia, and belching.3 In fact, only 40% of pa-
tient 65 years or older reported typical symptoms in an evaluation of 600 patients with
erosive esophagitis.12 In another study, older patients with Barrett esophagus had
symptom scores that were comparable with that of control patients without reflux.12
Hence there are significant clinical implications to a delay in diagnosis. A systemic re-
view and meta-analysis identified more severe patterns of reflux and esophagitis in the
elderly despite no change in GERD symptoms.13
Beyond esophageal injury, elderly patients are also prone to GERD-associated
aspiration, which carries a significant risk of morbidity and mortality.14 Manometric
changes in the upper esophageal sphincter (UES) have included lower baseline pres-
sure, decreased relaxation, and increased pharyngeal contractility.15 Moreover, the
UES response to reflux is reduced.16 Laryngopharyngeal reflux (LPR), with or without
classic GERD, is associated with a significantly higher economic burden, with 5438$
per person compared with 971$ for GERD.17 Although it is likely that LPR is more com-
mon in the elderly, the absence of classical symptoms and limited objective testing in
the population makes it difficult to ascertain true incidence. Associated symptoms
include reactive airway disease, chronic cough, laryngitis, hoarseness, and voice
change.18
PATHOPHYSIOLOGY
The pathophysiology of GERD in the elderly is multifaceted. Changes include struc-
tural and dynamic changes at the level of the lower esophageal sphincter (LES),
increased incidence of hiatal hernias that are often larger than younger cohorts,
increased gastric refluxate, ineffective esophageal clearance, and luminal stasis in
the setting of esophageal dysmotility.4 Other factors include limitation in activities of
daily living and musculoskeletal postural changes.6
Larger hiatal hernias and lower LES pressures have also been reported more
frequently in an elderly population.19 Frequent transient lower esophageal sphincter
relaxation (TLESRs) are part of pathophysiological underpinnings for the increased fre-
quency of GERD. There is no clear association between age and TLESRs,20 but the
polypharmacy commonly seen in the elderly includes many medications that have
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been associated with more frequent TLESRs. These include nitrates, calcium channel
blockers, benzodiazepines, anticholinergics, antidepressants, and lidocaine.21
Broadly combined into presbyesophagus, the subtle changes in the esophageal
body are less clear. Retrospective reviews of various institutional experiences asso-
ciate aging with major motility disorders.22–25 Elderly patients with endoscopic or
impedance evidence of GERD are more likely to have an esophageal motility disorder
on manometry (44% 70 years or older vs 13% 17–39 years old)26 and lower rates of
swallow-induced peristalsis on impedance study. Increasing age was also associated
with more frequent reflux but less severe reflux episodes.20,27 The clinical implications
of cellular changes in autopsy studies indicating decrease in ganglionic cells and
increased lymphocytic infiltration in esophageal biopsies when compared with young
individuals are uncertain.28 Yet similar changes have been noted in major esophageal
motility disorders.29
In additional to mechanical stasis the reflexive ability to increase salivary bicar-
bonate is diminished in the elderly despite the absence of change in volume and
baseline bicarbonate levels.25 This weakened neutralizing salivary secretion is paired
with increased gastric refluxate in the setting of a growing epidemic of obesity,
which has not spared the elderly and makes reflux worse via multifactorial
pathways.30
TESTING
The low risk of complications from esophagogastroduodenoscopy (EGD) are often
pitted against the odds of an endoscopic finding that would validate the diagnosis
or ideally change medical management. Many would favor of an empirical proton
pump inhibitor (PPI) trial instead of an EGD in many scenarios. This is most appli-
cable to a primary care setting and young otherwise healthy patient population.
PPI trial is an acceptable option, as it is available, noninvasive, and inexpensive,
with sensitivity ranging from 68% to 83%.4,11,31 Typically, EGDs are recommended
to assess refractory symptoms or to patients who are unable to wean off medical
therapy or patients who are unable to wean off medical therapy or to assess
complications.
Given atypical symptoms or absence of symptoms in the elderly and a higher
prevalence of severe disease and complications, EGD is encouraged earlier in
the elderly, as it helps complete a thorough workup and avoids delay in diag-
nostic care. Although there is no guideline recommendation to support EGD
in this group yet, visual evaluation has the added advantage of assessing the
presence of and degree of esophagitis and identifying and treating GERD com-
plications including strictures and Barrett esophagus (with or without
malignancy).3
Esophageal functional testing with pH and impedance is the most informative test in
GERD. Metrics of disease continue to be defined and validated, with esophageal acid
exposure time being the most reliable thus far. Impedance monitors allow for a
detailed functional analysis of distal and proximal esophageal reflux events.32 These
results should be interpreted with caution, as normative values may not apply to a geri-
atric population.33,34
Radiographically, a well-performed double contrast esophagram complements
an endoscopy and can identify a subtle stricture that would have otherwise
been missed. Esophagrams may identify changes associated with esophagitis
yet they lack the necessary sensitivity for a screening test.3 Although they are
financially disincentivized and being performed less frequently, esophagrams
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continue to play a role in tailoring antireflux surgery and improving outcomes via
the careful assessment of gastroesophageal junction (GEJ) anatomy relative to
the diaphragm and other anatomic details. They can also add informative data
on patients with postoperative symptoms. Additional predictive metrics include
barium tablets, where a delay in the 13-mm tablet may suggest a tight
fundoplication.35
Evaluating LPR is challenging. Beyond the field of view of a standard EGD, structural
evaluation with laryngoscopy is essential but findings typically associated with GERD
are nonspecific. Functional testing such as esophageal pH/impedance has poor
sensitivity. Oropharyngeal pH testing and salivary pepsin evaluation are not as widely
adopted due to unclear utility. More accurate sensors and indices that are objective
and validated are needed to help guide some of the more targeted chemical and
pH testing of proximal pharyngeal reflux.36
TREATMENT
Lifestyle Modifications
The efficacy of lifestyle modifications is not limited to young patients. Elderly patients
can benefit a great deal from minor changes in their dietary and sleeping habits. The
latter includes head of bed elevation, ideally by using wedge mattress inserts.37–39
Moreover, appropriate utilization of positive ventilation in patients with obstructive
sleep apnea has been shown to help reduce nocturnal reflux.40 Effective dietary
changes include avoiding late evening meals and meals with a high fat content.41
Finally, weight gain increases frequency and severity of GERD. Hence, weight loss
is a recommended and effective measure to reduce reflux.30
Medical Therapy
Antacids are very effective in the rapid treatment of pyrosis symptoms (typically 30–
60 minutes) but their long-term efficacy is limited. They are readily available over
the counter in various formulations that have comparable efficacy. Uniquely a few for-
mulations have the added benefit of an antireflux barrier in the form of an alginate
raft.42 Although antacids are typically considered safe, there are some side effects
that are more concerning in elderly patients. Antacids can interfere with absorption
of other essential medications, have undesirable effects on bowel habits (aluminum
and calcium containing agents worsening constipation), and may increase overall
salt intake (with preparations containing sodium bicarbonate). Milk alkali syndrome
can occur, albeit rarely, with increased dosing. This is often exacerbated by concom-
itant use of angiotensin-converting enzyme inhibitors, thiazides, and nonsteroidal anti-
inflammatory medications. Finally, there are some reports associating aluminum
containing antacids with Alzheimer disease.43
Antihistamines (H2 receptor antagonists [H2RAs]) are a step-up therapy. They are
commonly used for reflux and are effective over an extended period of time, yet
they are less potent than PPI and have a shorter duration of action. In a meta-
analysis of 7000 patients, erosive esophagitis was healed 84% versus 52% on PPI
versus H2RAs.44 Although there is some concern over tachyphylaxis, the effective
use of H2RA as solo therapy or additive therapy for nocturnal symptoms is common.
Beyond recent concerns for impurities in ranitidine formulations, there are some con-
cerns of mental status changes associated with H2RAs. These are most relevant to
patients with renal and hepatic impairment. Cimetidine is less commonly used than
other H2 receptor antagoniists in part because of its effect on cytochrome enzymes,
and this can have significant downstream consequences for elderly patients with
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Inc. Todos los derechos reservados.GERD and Barrett Esophagus in the Elderly 21
polypharmacy, particularly in combination with medication with narrow therapeutic
windows.45
Potent suppression of gastric acid production with PPI is the most effective medical
treatment of GERD regardless of age. Although plasma clearance decreases with age,
no dose deescalation is necessary in elderly patients.46 Pantoprazole and esomepra-
zole pharmacokinetics seem to be relatively unaffected by age.47 Direct comparison
between various PPI has indicated slight superiority for esomeprazole in healing of
mucosal erosion,48 and omeprazole-sodium bicarbonate in achieving prolonged intra-
gastric suppression,49 but there are no substantial clinical differences.3
Management of GERD in the elderly predicates on the principle of the least invasive
intervention with the greatest potential benefit. Common side effects of PPI are mild
and include headaches, nausea, abdominal pain, change bowel habits, rash, and
dizziness. Typically considered a mainstay of treatment of GERD, PPIs were widely
prescribed and likely overutilized. There is momentum to move away from a standard-
ized approach, given growing literature on potential long-term side effects.50 This liter-
ature includes retrospective cross-sectional studies, randomized control trials, and
metanalysis with conflicting data. Side effects can be grouped into malabsorptive, in-
fectious, and other rare complications.
Gastric acid suppression theoretically leads to vitamin B12 deficiency through an
inability to liberate intrinsic factor. This is more profound in elderly who are at a greater
risk of pernicious anemia. Associations between vitamin B12 deficiency and PPI use
have been limited to case series and retrospective reviews.51–53 Current guidelines
and expert opinion do not advocate for serum vitamin B12 measurements.4 Other
concerns include decreased absorption of divalent minerals such as calcium and
magnesium. The concern with calcium pertains to the risk of poor bone health, which
is particularly concerning in postmenopausal women who are at risk of osteoporotic
fractures.54 There are also some retrospective studies associating PPIs with increased
cardiovascular and renal events. Beyond checking vitamin D levels, there are no data
to support additional testing.
In the absence of gastric acid barrier there is a theoretic increased risk of infection.
Community-acquired pneumonia and Clostridium difficile infections have been most
widely studied. Respiratory infections are postulated to be related to increased bac-
terial colonization in the upper gastrointestinal tract.55 Despite the publication of ran-
domized control trials and meta-analysis the results continue to be mixed.54 The risk
with enteric infections, particularly C difficile is more pathophysiologically plausible
and data supported.56
Dementia and altered mental status have been suggested in retrospective cohort
studies but not validated in prospective case control studies.57–59 Autoimmune inter-
stitial nephritis is a well-categorized entity that represents a very rare complication of
PPI use.60
An 8-week course of any PPI once a day achieves healing of esophagitis in 73% to
91% of patients.61 Elderly patients may require greater acid suppression for esopha-
gitis healing,62 and relapse in the elderly can be as high as 90% on stopping PPI ther-
apy.63 Nonetheless, overprescribing PPIs and the failure to discontinue them affects
66% of hospital admissions. It likely represents a significant proportion of the huge
health care cost associated with reflux. Early appropriate discontinuation of PPI and
H2A has now become a quality metric with several societal and institutional
initiatives.64
Several prokinetics have been considered and evaluated in the treatment of GERD,
with the purported mechanism of increasing gastric acid secretion and improving LES
tone. Until recently the only FDA-approved prokinetic agents were erythromycin and
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metoclopramide. The dopamine antagonist, metaclopramide, has been shown to in-
crease LES pressure and improve gastric emptying.65 There is a black box warning
for idiosyncratic reaction of irreversible tardive dyskinesia. Moreover, it has been
associated with muscles tremors, spasms, agitation, anxiety, insomnia, and drowsi-
ness in up to one-third of patients.66 Domperidone is not available in the United States
and shares many prokinetic properties with metoclopramide but has a higher safety
profile given limited central nervous system interaction.67
Surgical Therapy
In patients who forego medical therapy (in part due to polypharmacy) or are refractory
to medical therapy, surgical repair of the hiatal defect and the creation of a more effi-
cient antireflux barrier is possible. A laparoscopic fundoplication is the standard of
care. In addition to decades in refinement of surgical technique, personalized surgical
planning with a presurgical evaluation is widely adopted. Structural examination in-
cludes esophagram and endoscopy, whereas preoperative functional testing includes
pH/impedance testing, manometry, and a gastric emptying study. Randomized con-
trol trials have identified comparable efficacy between PPI therapy and laparoscopic
fundoplication.68 Results have been durable over 5 years69 with only a minority
requiring reinitiation of PPI.70 Durability beyond the first decade and need for redo fun-
doplication are less applicable in an elderly population.19,71–73 Although some data
suggest that elderly are more susceptible to earlier complications,74–76 studies with
open and laparoscopic fundoplication show no increase in mortality or morbidity in
this age group,77–79 which further supports the need for careful patient selection
and a complete and through presurgical evaluation.
Endoscopic Therapy
Endoscopic antireflux therapy provides a middle ground between surgical and medi-
cal therapies and has been a target of extensive biomedical advancement. Many de-
vices with promising early data have gone out of stock due to a lack of durable benefit
and unacceptable complications. Available options include augmentation of the GEJ
through submucosal radio frequency ablation scarring (Stretta) and endoscopically
placed gastroesophageal junction t-fasteners (transoral incisionless fundoplication).4
These minimally invasive interventions have varying degrees of evidence and societal
support. At present insurance coverage and careful selection of patients will allow us
to best identify a subset of elderly patients who would benefit from such interventions
and avoid some of the risks associated with surgical or medical therapy.
BARRETT ESOPHAGUS
In addition to esophagitis, strictures, Barrett esophagus, and esophageal adenocarci-
noma (EAC) are potential complications of long-term GERD.80 Incidence of all seems
to increase with age.81–85
Barrett esophagus is defined as metaplastic growth of specialized intestinal epithe-
lium that appears as columnar mucosa in the distal esophagus on an endoscopic eval-
uation. The incidence of Barrett esophagus seems to increase with age,86 in part due
to pathophysiological barrier breakdown at the level of the esophagogastric junction
and progression in size of the hiatal hernia. This validates epidemiologic data indi-
cating peak incidence of EAC in the sixth and seventh decade of life.87 The sensitivity
of symptoms to suggest Barrett esophagus is low; in fact almost one-third of elderly
patients are asymptomatic.88
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Various societies have adopted an age threshold (commonly 50 years) as a risk fac-
tor that is incorporated into determining patients who should undergo screening.
These guidelines also advocated for an age limit on screening.89–91 This is partly
due to increasing comorbidities and nonesophageal cancer-related mortality in the
elderly. A discussion regarding likelihood of survival over the next 5 years is recom-
mended. There is limited literature on the life expectancy of elderly men with Barrett
esophagus. In a recent cross-sectional study of 4252 veterans, a quarter of patients
were 80 years old or older. One-third of them had limited life expectancy at the time
of their Barrett esophagus diagnosis and a quarter of them died within 4 years of
diagnosis.92
Dysplasia remains the only readily available and reliable predictor of progression to
adenocarcinoma.93 Misattribution of inflammation to dysplasia is common94 and
might be more challenging in the elderly given concomitant esophagitis. In addition
to less frequently causing symptoms, esophagitis is typically more severe in the
elderly.9 It is therefore strongly encouraged that histologic risk assessment is delayed
until esophagitis is healed. On medical optimization the interval for surveillance de-
pends on degree of dysplasia: 3 to 5 years for nondysplastic Barrett esophagus and
6 to 12 months for Barrett esophagus with low-grade dysplasia (LGD). Endoscopic
ablation is an acceptable alternative in patients with LGD with reasonable life expec-
tancy. Patients with high-grade dysplasia are uniformly recommended to undergo
endoscopy therapy. The guidelines do not recommend different intervals based on
age.89–91
Esophagectomy remains a treatment of high-grade dysplasia and for endoscop-
ically untreatable adenocarcinoma. There is significant increased morbidity and
mortality associated with an esophagectomy in the elderly despite advances in
technique and postsurgical care.95,96 Because of the advent of effective and dura-
ble endoscopic esophageal sparing procedures, there are arguments to extend the
age limit of screening and testing.90 In fact studies have suggested a preferentially
improved 2-year survival rate for elderly patients treated endoscopically.97 The
outcomes of endoscopic and surgical therapies are significantly improved in
high volume centers.98 This is most applicable in elderly patients in whom early
detection of complications and management of comorbidities play a significant
part.
Identifying a potent chemoprophylactic agent that can reduce the progression to
advanced dysplasia and cancer has been actively sought. Many medications with
antiinflammatory or antineoplastic potential have been evaluated. Aspirin (ASA) has
chemoprophylactic properties against various gastrointestinal cancers.99,100 A recent
prospective multicenter trial, AspECT, found the greatest benefit was for a combina-
tion of high-dose PPI and ASA. It should be noted that although ASA toxicity is low,
there is a risk for bleeding, intestinal ulceration, and strictures.101 Several randomized
trials have recently found nearly double the risk of bleeding with no to little cardiovas-
cular benefit in patient receiving ASA chemoprophylaxis.102 USPSTF now recom-
mends a more tailored role for ASA that accounts for the weight of various bleeding
risk factors.103 Although chronic PPI use for chemoprophylaxis use in Barrett esoph-
agus has more evidence behind it, the use of ASA solely for chemoprevention in Bar-
rett esophagus remains controversial.
SUMMARY
As our population continues to age, the early diagnosis and optimal management
of patients with GERD becomes paramount. Maintaining a low threshold for
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Inc. Todos los derechos reservados.24 Otaki & Iyer
evaluating atypical symptoms in this population is key to improving outcomes.
Should patients develop complications including severe esophagitis, peptic stric-
ture, or Barrett esophagus then a discussion of medical, endoscopic, and surgical
treatments that accounts for patient’s comorbidities and survival is important. Ad-
vances in screening, surveillance, and endoscopic treatment of Barrett esophagus
have allowed us to dispel concerns of futility and treat a larger subset of the at-
risk population. Given that GERD persistently accounts for high per patient and
health care costs, it is essential we continue to improve the quality of our health
care delivery.
DISCLOSURE
P.G. Iyer: Research funding from C2 Therapeutics, Nine Point Medical, Exact Sci-
ences, Consultant: Medtronic, CSA Medical, Symple Surgical; F. Otaki has nothing
to disclose.
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